Ifosfamide metabolism and pharmacokinetics (review)

In this article the studies on the pharmacokinetics and metabolism of ifosfamide have been summarised. Ifosfamide is a pro-drug and requires metabolic activation to exert cytotoxic activity. The various metabolites determined after oral or intravenous administration of ifosfamide show a large inter- and intrapatient variability. Oral and intravenous fractionated treatment with ifosfamide exhibits a time-dependent increase in ifosfamide metabolic clearance which is explained by a mechanism of auto-induction of the hepatic oxygenase system. The pharmacokinetic parameters of ifosfamide do not correlate with age, sex and weight. Oral ifosfamide, at a dose higher than 1 g/m2, induces neurotoxicity in a high percentage of patients. In these cases the pharmacokinetics of ifosfamide were not aberrant. This implies that ifosfamide metabolites rather than the parent drug are likely to be responsible for the neurotoxicity. The development of more selective and sensitive analytical methodologies are necessary in order to go in more insight into the disposition of the active ifosfamide metabolites, including their clinical effects. This may lead to a further optimisation of the therapeutic use of ifosfamide.